Fracture incidence is a major health care problem in the Western world, and will have an increasing impact on health care as the elderly population increases over the next thirty years. Present costs now exceed 3 billion dollars annually and may increase to 20 billion dollars over the next thirty years. Previous reports have shown that long term administration of high dose estrogen therapy prevents bone loss in postmenopausal women, and retrospective studies have shown that previous estrogen treatment is associated with decreased numbers of fractures. However, there is concern about the occurrence of an increased incidence of uterine cancer and possibly breast cancer on high doses of estrogen. Progestogens undoubtedly reduce the incidence rate of uterine cancer to levels less than those of untreated women. But the use of progestogens needs careful follow up since C19 derivatives lower HDL cholesterol levels, and may adversely increase bone loss. Our project is designed to find the minimum dose of estrogen that will prevent bone loss, and to compare results with those in groups given a C21 progestogen alone, a combination of estrogen and progestogen, or placebo. We should be able to detect any antagonistic or synergistic effect of progestogens on bone. Multiple techniques for measuring bone density will be used, icnluding single and dual photon absorptiometry, total body calcium with regional skeletal density, computerized axial tomography and metacarpal morphometry. These different methods should allow us to measure changes in different regions of the skeleton and follow the separate responses of cortical and trabecular bone to hormones. The rate of bone loss will be compared with various biochemical markers, such as serum levels of bone GLA protein, vitamin D, estrogen, parathyroid hormone, calcitonin, and urine hydroxyproline excretion. Since no single test is diagnostic of rapid bone loss we will try to identify fast losers by a combination of tests using discriminant function analysis. We will also examine long term safety of the hormones by performing serial endometrial biopsies and measuring HDL cholesterol levels.